The Health and Environmental Sciences Institute, Washington, DC, USA.
National Centre for the 3Rs (NC3Rs), London, United Kingdom.
Environ Toxicol Chem. 2023 Apr;42(4):757-777. doi: 10.1002/etc.5584. Epub 2023 Mar 20.
Multiple in vivo test guidelines focusing on the estrogen, androgen, thyroid, and steroidogenesis pathways have been developed and validated for mammals, amphibians, or fish. However, these tests are resource-intensive and often use a large number of laboratory animals. Developing alternatives for in vivo tests is consistent with the replacement, reduction, and refinement principles for animal welfare considerations, which are supported by increasing mandates to move toward an "animal-free" testing paradigm worldwide. New approach methodologies (NAMs) hold great promise to identify molecular, cellular, and tissue changes that can be used to predict effects reliably and more efficiently at the individual level (and potentially on populations) while reducing the number of animals used in (eco)toxicological testing for endocrine disruption. In a collaborative effort, experts from government, academia, and industry met in 2020 to discuss the current challenges of testing for endocrine activity assessment for fish and amphibians. Continuing this cross-sector initiative, our review focuses on the current state of the science regarding the use of NAMs to identify chemical-induced endocrine effects. The present study highlights the challenges of using NAMs for safety assessment and what work is needed to reduce their uncertainties and increase their acceptance in regulatory processes. We have reviewed the current NAMs available for endocrine activity assessment including in silico, in vitro, and eleutheroembryo models. New approach methodologies can be integrated as part of a weight-of-evidence approach for hazard or risk assessment using the adverse outcome pathway framework. The development and utilization of NAMs not only allows for replacement, reduction, and refinement of animal testing but can also provide robust and fit-for-purpose methods to identify chemicals acting via endocrine mechanisms. Environ Toxicol Chem 2023;42:757-777. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.
多种针对哺乳动物、两栖动物或鱼类的雌激素、雄激素、甲状腺和类固醇生成途径的体内测试指南已经开发和验证。然而，这些测试资源密集且通常使用大量实验动物。开发体内测试的替代方法符合动物福利考虑的替代、减少和优化原则，这些原则得到了越来越多的支持，即向全球范围内的“无动物”测试范式转变。新方法学（NAMs）有很大的潜力来识别分子、细胞和组织变化，这些变化可以用来可靠且更有效地预测个体水平（以及潜在的种群水平）的效应，同时减少用于内分泌干扰的（生态）毒理学测试中的动物数量。在一次合作努力中，来自政府、学术界和工业界的专家于 2020 年开会讨论了鱼类和两栖类内分泌活性评估测试的当前挑战。继续这一跨部门的倡议，我们的综述重点关注当前使用 NAMs 识别化学诱导的内分泌效应的科学现状。本研究强调了使用 NAMs 进行安全性评估的挑战，以及为了减少其不确定性并增加其在监管过程中的接受度需要开展哪些工作。我们已经审查了当前可用于内分泌活性评估的 NAMs，包括计算、体外和 Eleutheroembryo 模型。新方法学可以作为危害或风险评估的证据权重方法的一部分，整合到不良结局途径框架中。NAMs 的开发和利用不仅允许替代、减少和优化动物测试，还可以提供稳健且适合目的的方法来识别通过内分泌机制作用的化学物质。环境毒理学与化学 2023；42：757-777。©2023 作者。环境毒理学与化学由 Wiley 期刊出版公司代表 SETAC 出版。
